Brain Function Decline

Brain Function Decline

Brain Function Decline


Risk Factors
Nutritional Approaches to Cognitive Decline
Suggested Supplementation



Aging humans tend to develop some degree of decline in brain (cognitive) function, and research shows this deterioration can occur as early as mid-20s.  Symptoms can include:

  • forgetfulness
  • decreased ability to maintain focus
  • decreased problem solving capacity

If left unchecked, symptoms can progress into more serious conditions, such as dementia and depression, or even Alzheimer’s disease.

The aging process profoundly impacts the brain in ways that can be observed on multiple levels, ranging from sub-cellularly to macro-structurally. In a broader sense, the physical structure of the brain as a whole deteriorates with age. Shrinkage and death of neurons, and reductions in the number of synaptic spines and functional synapses contribute to annual reductions of as much as 0.5% to 1.0% in cortical thickness (the cortex is the outermost layer of the brain) and sub-cortical volume in some regions of the brain.37

Specifically, even in healthy individuals, aging accounts for volume variances of 37% in the thalamus, which is involved in sight, hearing, and the sleep-wake cycle; 36% in the nucleus accumbens, which plays a major role in mood regulation (e.g. pleasure, fear, reward); and 33% in the hippocampus, a critical site for consolidation of short-term to long-term memory.38 Taken together, age related cognitive decline occurs in tandem with the physical degradation of brain structure. Thus, conserving cognitive vigilance into late life requires early and aggressive intervention to preserve the brain in its youthful physical and functional state.

Fortunately, lifestyle changes, cognitive training, and nutritional interventions have been shown to reduce the rate of intellectual decay and potentially reverse age-related cognitive decline.



Cognitive decline does not affect all individuals equally.  The rate and severity of cognitive decline are related to a variety of factors, including:

  • Oxidative stress and free radical damage16,17,18 
  • Chronic low-level inflammation19
  • Declining hormone levels like estrogen, testosterone, DHEA, pregnenolone20
  • Inner arterial lining (endothelium) dysfunction21
  • Insulin resistance26
  • Excess body weight22
  • Suboptimal nutrition23
  • Loneliness, lack of social network, and high stress25


Biological Risk Factors Contributing to Cognitive Decline

Oxidative Stress

The brain is particularly susceptible to oxidative damage since it consumes roughly 20% of the oxygen used by the entire body, and because it contains high concentrations of phospholipids, which are especially prone to oxidative damage in the context of high metabolic rate.45 As we age, there is a significant and progressive increase in the level of oxidatively damaged DNA and lipids in the brain; this is true even for healthy individuals.46 Over time, this free radical damage leads to the death of neurons.

Numerous studies have implicated oxidative stress in the pathology of mild cognitive impairment and Alzheimer’s disease alike.47,48,49



The inflammatory process in the brain is unique in that the blood-brain barrier (BBB) (tight layer of endothelial cells that separates the brain from regular systemic circulation), during healthy conditions, prevents the infiltration of inflammatory agents and allows only select nutrients and small molecules into the central nervous system (CNS).54 However, chronic systemic inflammation induced by stimuli such as cigarette smoking, obesity, disrupted sleep patterns and poor dietary habits compromises the integrity of the BBB, allowing irritants to enter the brain and stimulate the production of inflammatory cytokines, such as IL-1β, IL-6 and IL-18.55 Inside the CNS, these cytokines impair neurogenesis, the process by which new neurons are generated.56,57,58,59 Aside from inhibiting neurogenesis, some inflammatory cytokines, such as IL-1β, IL-6 and TNF-α damage and destroy existing neurons.60,61


Hormonal Imbalance

Distributed throughout the brain are steroid hormone receptors which function to regulate the transcription of a vast array of genes involved in cognition and behavior.68  When hormonal imbalances or deficiencies disrupt receptor activation, cognitive deficits and emotional turmoil are the result.

  • Estrogen. Animal models indicate that experimentally-induced alterations in the levels of steroid hormones, particularly estradiol, in the brain cause significant behavioral changes observable within minutes, leading some researchers to conclude that steroid hormones actually have the capacity to function directly as neurotransmitters in the central nervous system.69 In humans, suboptimal (low) levels of estradiol are associated with decreased scores on standardized assessments of cognition in both men and women.70Postmenopausal women with higher levels of endogenous estradiol also have better semantic memory than do those deficient in the estrogen.71 Accordingly, postmenopausal women treated with estradiol displayed improvements in executive function compared to those taking a placebo.72
  • Testosterone. Maintaining optimal levels of testosterone can help preserve cognitive ability as well. In a study involving over 500 aging men and women, higher levels of testosterone were linked with better performance on the Mini-Mental State Examination at baseline. Men with the lowest levels of testosterone at the beginning of the study period were more likely to exhibit a sharp decline in cognitive ability over the following two-year period as well.73 Several other studies also conclude that testosterone levels are positively associated with multiple aspects of cognitive function.74,75
  • Dehydroepiandrosterone (DHEA). Age-associated decline in levels of the adrenal hormone dehydroepiandrosterone (DHEA), which is very active in the central nervous system,80 are also tied to worsening cognitive performance.81 In a study involving over 750 aging subjects, Mini-Mental State Examination (MMSE) scores were significantly associated with levels of DHEA-s, the sulfated metabolic derivate of DHEA, which is more highly concentrated in humans. Moreover, those individuals with the lowest levels of DHEA-s at baseline displayed greater cognitive decline over time than those with higher initial levels.82 In a separate community-based study involving nearly 300 healthy women, levels of DHEA-S correlated positively with superior executive function, concentration, and working memory.83 Accordingly, in a double-blind, placebo controlled clinical trial, six-months of supplementation with 25 mg of DHEA daily improved measures of cognitive function, especially verbal fluency, in aging women.84
  • Pregnenolone. Another neurosteroid, pregnenolone, is also involved with a number of cognition-related functions within the brain. For example, experimental studies indicate that pregnenolone modulates neurotransmitter signaling through interaction with select receptor sites, which translates to improvements in long-term memory in rodents.85,86 In human clinical trials, supplementation with pregnenolone improved cognition in subjects with neurological disorders.87 Additionally, levels of pregnenolone metabolites are reduced significantly in the prefrontal cortex, an area involved with higher-order processing, in Alzheimer’s disease patients, leading some researchers to speculate that pregnenolone levels may be relevant in the pathology of the disease.88


Cerebrovascular Health

The brain depends on the carotid arteries to obtain the oxygen and nutrient-rich blood that it needs to sustain its high rate of metabolic activity. Like other blood vessels, the carotid arteries and their subsidiaries (smaller branches) are susceptible to endothelial dysfunction, dysregulation and damage to the delicate cells that line our blood vessels. If the integrity of the blood vessels that supply the brain is compromised, cognition suffers as a result.

  • HDL levels. HDL serves to shuttle cholesterol from the blood vessel walls back to the liver for excretion, and thus insufficient levels of HDL are associated with increased endothelial dysfunction and arterial plaque deposition. Studies have linked low HDL levels with declining brain health and function.
  • Homocysteine. Homocysteine is an endogenous amino acid derivative which damages the endothelial cells that line the inside of blood vessels and contributes to the pathogenesis of atherosclerosis and vascular dysfunction.95 Elevated homocysteine has been linked with reduced blood flow to the brain,96 memory impairment,97 poorer global cognitive function,98 smaller overall brain volume,99 and increased silent brain infarcts (subclinical stroke-like blood vessel occlusions in the brain).100
  • Hypertension. Small, delicate capillaries, like those that perpetuate the flow of blood throughout the brain, are particularly susceptible to damage caused by elevated blood pressure. Chronic hypertension leads to the breakdown of cerebro-capillaries, a condition associated with the development neurodegenerative diseases and cognitive impairment.103 Evidence suggests that blood pressure of 115/75 mmHg significantly reduces the risk for cardiovascular disease,107 and thus may be an ideal target for those who wish to maintain optimal cognitive performance as well.


Diabetes and Insulin Resistance

Due to the high metabolic demand for energy in the brain, even small disturbance in glucose metabolism can noticeably impact cognitive performance. Diabetes (hyperglycemia) has been linked with lower levels of neuronal growth factors,108 decreased brain volume,109 and higher incidence of all types of dementia.110

Researchers in another study compared MRI-assessed manifestations of cerebral degeneration in 89 non-demented subjects with type-2 diabetes to 438 age-matched healthy controls over a three-year period. Individuals with diabetes displayed increased progression of brain atrophy, and performed less well on tests of cognitive performance and learning. The investigators concluded that “our data show that elderly patients with [type-2 diabetes] without dementia have accelerated progression of brain atrophy with significant consequences in cognition compared to subjects without [type-2 diabetes]. Our findings add further evidence to the hypothesis that diabetes exerts deleterious effects on neuronal integrity.”112



Adipose tissue secretes molecules that directly influence multiple functions within the brain.114 There is a clearly established reciprocal relationship between adiposity (amount of body fat) and overall brain volume and cognitive function. In other words, as bodyweight increases, brain volume drops and cognitive function worsens.115,116,117,118

In a study utilizing MRI brain imaging technology to explore the link between obesity and brain volume, researchers discovered that visceral abdominal obesity in particular was associated with deteriorating brain structure. This was true even in individuals without pre-existing cognitive deficits. The findings were statistically significant and independent of vascular risk factors and overall BMI. 119

Similar findings were reported by another group, but this time in 700 patients with a prior diagnosis of Alzheimer’s disease or cognitive impairment. Investigators identified a strong correlation between higher BMI and brain volume deficits in the frontal, temporal, parietal, and occipital lobes. It was concluded that “cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia.”120


Psychological Risk Factors Contributing to Cognitive Decline

Anxiety and Stress

Research in patients with anxiety has shown that, compared to non-anxious control subjects, those with high-anxiety levels must exert greater effort (dedicate more brain resources) to maintain the same level of performance on cognitive tests.126 More severe anxiety is also predicative of earlier conversion from mild cognitive impairment to Alzheimer’s disease.127 In men, even subclinical (low-level) anxiety is tied to cognitive impairment.128

Excessive stress leads to cognitive dysfunction as well. In a study involving 36 women between the ages of 25 and 53, those with the highest work-related stress levels displayed decreased attention and visuo-spatial memory.129 Likewise, in a cohort of 811 aging men, subjects reporting higher stress levels scored lower on the Mini-Mental State Examination than their low-stress counterparts. This indicates that “psychological stress had an independent inverse association with cognition…130

Meditation is an effective method for relieving stress. With the connection between stress and cognitive dysfunction in mind, researchers studied the effects of an 8-week audio-guided meditation program on cerebral blood flow and cognition in 14 subjects with memory problems. Tests revealed that meditation significantly increased cerebral blood flow in several major brain regions. Improvements in tests of verbal fluency and logical memory were attributed to meditation as well.133



An intimate relationship exists between depression and cognitive dysfunction. Many studies have closely examined this link and allude to the intertwinement of these two conditions, rather than a causal effect of one on the other. Interestingly, depression seems to worsen cognitive dysfunction, but poorer cognitive health predisposes aging individuals to depression as well.134

Continuing research has lead to the delineation of “depression-associated reversible dementia,” which is cognitive impairment associated with depression that subsides upon improvement of depression. Nonetheless, in a study of 57 elderly subjects with major depression, those who displayed depression-associated reversible dementia were nearly five times more likely to develop true dementia over a roughly three-year period.136


Social Network and Personal Relationships

Several studies have suggested that maintaining a large network of friends and other personal relationships, and regularly engaging in social and productive activities is associated with a decreased risk of cognitive decline.139,140 Conversely, social disengagement, defined as having very few or no social relationships, is a strong risk factor for cognitive decline.141

Social integration, defined by marital status, volunteer activity, and frequency of contact with children, parents, and neighbors, conveys a memory preserving effect in elderly adults. Over a six-year period, memory among those with the lowest level of social integration declined at twice the rate of subjects with the higher levels of social integration.146

Maintaining close ties with friends and loved ones, and being involved in various group-oriented activities, especially outdoors, is an effective method for stimulating and maintaining your brain as you age.


Mental and Physical Activity

The brain consists of a vast network of approximately 90 billion (109) neurons interconnected by 1,000 trillion (1015) synaptic junctions.147 Each mental and physical task that we perform stimulates this massive network in a unique way. Regular stimulation of diverse synaptic pathways by engaging in a wide range of mentally and physically challenging activities directly influences our ability to learn.

Physical Activity and Brain-Derived Neurotrophic Factor

A critical driving force behind neural plasticity (and therefore overall cognitive function) is a protein called brain-derived neurotrophic factor, or BDNF. BDNF acts upon areas of the brain involved in learning, memory, and higher-order thinking to stimulate genesis of new neurons, survival of existing neurons, and synaptic adaptation.151,152,153 Low levels of BDNF are observed in a variety of brain disorders, including cognitive decline, depression, dementia, and Alzheimer’s disease.154,155

Physical exercise is known to enhance cognitive function in humans and other animals, and many researchers now believe that an increase in levels of BDNF induced by exercise mediates this improvement.156,157,158 Several studies have demonstrated that moderate to high intensity aerobic or anaerobic exercise induces sharp (intensity-dependent) increases in BDNF levels in humans.159,160  For example, post-exercise spike in BDNF levels corresponded with a 20 percent improvement in short-term memory.164

These findings highlight the importance of not only engaging in exercise routines, but leading a generally active lifestyle as well in order to promote overall brain health.

Mental Activity, Brain Plasticity, and Cognitive Reserve

Neural plasticity, the dynamic ability of the brain to adapt and respond to novel stimuli in a unique and reinforceable way, is a pivotal aspect of cognition. Plasticity serves as a key medium for the effects of practicing a physical activity – i.e. getting better at a physical task over time. As we practice an activity repetitively signals are transmitted through the brain in a specific pattern over and over again. This redundant signaling ultimately strengthens the connections between neurons in the signaling pathway required to execute the task, leading to greater efficiency and accuracy of signal transmission.

An important limitation of physical practice, though, is that improvements in ability are generally confined to the task being practiced. In other words, practicing tennis does not increase proficiency in bowling. Repetitive mental stimulation, on the other hand, exerts domain-wide improvements that impact other tasks as well. To elaborate, practicing a mentally challenging activity that requires utilization of higher-order cognitive processes, playing chess for example, can improve fluency in other activities that require similar cognitive processes, like driving a vehicle.168,169

Brain plasticity also serves as a prerequisite for a more global effect known as cognitive reserve. This phenomenon arises from, and is dependent on, synaptogenesis – the formation of new synapses, the hallmark physical effect of mental training.  Cognitive reserve is measurable as a function of life experiences and studies have shown that cognitive reserve scores correlate with overall cognitive function in an aging population.170 

The introduction of novel cognitive stimuli encourages the brain to establish new neural networks through synaptogenesis, which can then be used to bypass breakdowns in other neural networks arising from age-related or pathological deterioration in brain circuitry.

Plasticity is an intrinsic property of the brain maintained throughout life; and so cognitive stimulation and training enhance cognitive reserve and convey protection against loss of brain function regardless of age.173 In a study including nearly 500 individuals with clinical cognitive impairment, computerized cognitive training significantly improved several measures of cognitive function.174 Improvement was still evident up to three months post training in some cognitive assessments. Moreover, as little as two hours of cognitive training initiates structural changes in the brain suggesting that those who chose to challenge their intellectual capacity reap the benefits instantaneously.175

Speaking more than one language is also a strong inducer of plasticity and cognitive reserve. Learning a second language requires the brain to constantly categorize information in ways that are unnecessary when only a single language is spoken; this establishes numerous new neuronal communication streams. In a study of more than 200 individuals clinically likely to have Alzheimer’s disease, being bilingual was found to delay that onset of symptoms by over five years, and delay diagnosis by nearly four and a half years relative to monolingual speakers.177

Cognitive stimulation and training also benefit the brain by enhancing cerebral blood flow. Mozolic et al have shown that an eight-week attention and distractibility cognitive training program significantly increased blood flow to the prefrontal cortex, a brain region involved in personality expression and decision making. The control group in this study, who were exposed to education material, but not intensive cognitive training, displayed no increase in cerebral perfusion.178

A lifestyle incorporating frequent physical exercise, continual learning, and regular cognitive stimulation is likely to be the most effective means for preserving, and possibly enhancing, cognitive function at any age.



Dietary Considerations for a Healthy Brain

The exceptionally high rate of metabolism in the brain makes it particularly responsive to the nutritional content of the diet. Healthy dietary habits ensure that food is an excellent source of nutrients that serve to support the brain both structurally and functionally.  Numerous studies have identified high intakes of simple sugars and saturated fats as being especially deleterious for brain health.194,195,196 Transitioning to a slightly calorie-restricted Mediterranean diet high in mono- and poly- unsaturated omega-3 fats, fiber, and polyphenols will provide the brain with nutrition to function at high capacity and efficiency.

Some dietary considerations that may be easily overlooked provide substantial brain benefits as well.

Calorie Restriction

Calorie restriction is the restriction of caloric intake to a level modestly below normal, typically 20% to 30% less, but the diet should be dense with micronutrients to maintain optimal nutrition. Caloric restriction is well-known for its ability to induce favorable changes in peripheral insulin sensitivity, which enhances insulin signaling in the central nervous system. The brain relies heavily on proper insulin signaling for a variety of functions that impact cognition, and so it is not surprising that caloric restriction has been shown to benefit cognitive function in many animal and human studies.197,198

Caloric restriction also boosts levels of several neurotrophic factors, including BDNF, and thus creates an ideal environment for plastic adaptation of the brain in response to mental stimulation.200

Mediterranean Diet

A great deal of scientific literature validates the Mediterranean diet as a staple for those concerned with cardiovascular health, cognitive health, and longevity. The diet centers on “good” fats – mono- and poly-unsaturated fats, especially omega-3’s and olive oil, multi-colored fruits and vegetables, and moderate red wine consumption.201,202  Adherence to the Mediterranean diet has been linked with improved insulin sensitivity,203 lipid metabolism204, blood pressure,205 reduced risk of developing cancer206 or metabolic syndrome,207 as well as an overall decrease in mortality.208, 209

Moderate Caffeinated Coffee Consumption

Coffee is an excellent source of antioxidant and neuroprotective compounds.226,227,228,229 However, it has been suggested recently that the antioxidant compounds in coffee may synergize with caffeine to enhance the protective effect against brain pathology, and that decaffeinated coffee does not provide the same level of neuroprotection observed with caffeinated coffee.230 Accordingly, a study which followed nearly 700 elderly men for a 10-year period revealed that coffee consumption, roughly equivalent to three cups daily, was associated with a 4.3 fold slower rate of cognitive decline when compared to those subjects who did not drink coffee.231

A team of Scottish researchers recently found that coffee consumption was tied to superior reading ability and higher scores on some other cognitive assessments in a cohort of over 900 healthy adults.232

Moreover, a level of evidence that is strongly suggestive has accumulated indicating that caffeine itself exerts a variety of protective and augmentative effects in various cognitive domains.233,234,235,236  In addition to preserving cognition, coffee consumption may also protect against type 2 diabetes and some cancers.240,241 Black coffee or espresso appear to be superior choices when selecting a coffee beverage for health benefits, since adding sugar or non-dairy creamer has been shown to blunt the ability of coffee to increase the levels of antioxidants in circulation.242

Nutraceuticals to Support Brain Health

Optimal neuroprotection and cognitive preservation often require micronutrient intakes in excess of those obtainable in a diet, or intake of specialized nutrients not common in most foods.

Many nutrients known to modulate physiological process important for brain health have been shown to slow cognitive deterioration, or enhance mental performance.

Fish Oil

Phospholipids are an integral component of all cells in the body, without which the integrity of cell membranes would fail, as would cellular function. In the brain omega-3 fatty acids are incorporated liberally into cellular phospholipid bilayers; DHA alone accounts for 40% of the phospholipid content of neuronal membranes.243Along with EPA, DHA plays a central role in neurotransmitter signaling and synthesis, and together the omega-3 fatty acids modulate numerous aspects of cognition and behavior.244,245,246

Evidence suggests that the typical Western diet is severely deficient in beneficial omega-3’s, and supplies omega-6’s in excess, which creates a fatty acid milieu that promotes inflammation and contributes to several age related degenerative diseases.247 Numerous studies have concluded accordingly, indicating that supplementation with omega-3 fatty acids optimizes cognitive health.

A study involving nearly 1,500 subjects found that daily omega-3 supplementation was independently associated with a dramatic reduction in cognitive decline over a 1.5 year period in an aging study population, compared to those not taking omega-3 supplements. Importantly, this study also found that dietary fish consumption was not associated with cognition, while omega-3 supplements were, highlighting the superiority of supplementing with omega-3’s for supporting brain health.249

In addition to the numerous studies that have associated increased dietary omega-3 intake with better cognitive performance,250,251 a more detailed study confirms the principle role the role of DHA in mediating this improvement. Researchers assessed serum phospholipid levels in 280 middle-aged (35 – 54) healthy study volunteers, which were then correlated to cognitive function. It was found that subjects with the highest serum levels of DHA performed significantly better in multiple domains of cognition than their cohorts with lower DHA levels.


Wild Green Oat Extract 

By age 45, the brain’s levels of dopamine begin to diminish.352  This not only makes people feel older, but is also involved in accelerated brain aging.

Dopamine depletion is largely caused by rising levels of the MAO-B enzyme. The ensuing dopamine deficiency strikes the brain’s signaling system. The tragic result is cognitive decline, destruction of brain cells, reduction of youthful vigor/sexual desire, progression toward Parkinson’s/neurological disorders, and a decreased lifespan.353-358

Scientists have identified a bioactive extract of wild green oat that not only inhibits MAO-B and the resulting breakdown of dopamine, but enhances dopaminergic neurotransmission that normally declines with aging. These protective actions enable more dopamine availability for use by brain cells.

In human studies, the effects of wild green oat extract resulted in increased focus and concentration, processing speed, executive function, and working memory as well as other parameters of enhanced dopaminergic transmission.359,360


Polyphenols and Anthocyanins

Polyphenolic antioxidants, such as resveratrol from grapes, catechins from green tea, and anthocyanins from blueberries are among the strongest naturally occurring free radical neutralizers, and several laboratory in vitro studies have confirmed the neuroprotective properties of these antioxidants.

  • Blueberries. Multiple animal studies have provided mechanistic insights into the well-documented brain health benefits of blueberry constituents. In addition to strongly attenuating neural oxidative stress, blueberry components also inhibit acetylcholineesterase (AChE), an enzyme responsible for catabolizing the important neurotransmitter acetylcholine, thus preserving acetylcholine-related memory and learning.258 Blueberry supplementation also stimulates neurogenesis and enhances neuronal plasticity (adaptability) in the hippocampus, the region of the brain chiefly affected by Alzheimer’s disease.259 Other research has revealed that blueberry compounds may optimize cognitive performance through modulation of genetic expression within the brain.260
  • Tea Polyphenols. Interest in studying components of tea in the context of brain health was generated by publication of epidemiological evidence which linked increased tea consumption with superior cognitive function in aged populations.266,267 Investigations were fruitful in that they led to the elucidation of powerful tea constituents, including epigallocatechin-3-gallate (EGCG), and other phenolic antioxidants, and findings that these compounds possess tremendous disease modifying potential in Alzheimer’s disease and the ability to preserve cognition in healthy aging individuals, and animals.268,269,270
  • Resveratrol. A multitude of evidence suggest that resveratrol extends lifespan in experimental settings, likely by mimicking the genetic effects of calorie restriction,283 numerous publications also highlight various roles for resveratrol in optimizing brain function.

Resveratrol may benefit the brain via mechanisms including increased synthesis of the growth factors IGF-1284and BDNF285 in the hippocampus, suppressing formation of inflammatory metabolic products within the brain,286,287 reinforcing the integrity of the blood-brain-barrier,288 and optimizing overall brain metabolism.289Other studies have shown that resveratrol supplementation preserves cerebrovascular integrity with aging,290and protects the brain after traumatic brain injury as well.291



Inside the central nervous system B-vitamin-dependent reactions are responsible for ensuring the proper function of a vast array of neurochemical processes. When levels of B-vitamins, especially B6, B12, and folic acid, are insufficient to optimally support these reactions consequences such as impaired neurotransmitter synthesis and neurocapillary-damaging hyperhomocysteinemia can result.294

Multiple human studies have associated low plasma levels of B-vitamins, and even subclinical deficiencies, with cognitive decline and dementia.295,296,297  The brain may be the first organ affected by insufficient intakes of various other B-vitamins as well, including pantothenic acid, riboflavin, and nicotinamide, since these nutrients are important intermediaries in the mitochondrial oxidative phosphorylation (OXPHOS) process, a series of reactions by which chemical energy in the form of adenosine triphosphate (ATP) is produced.


Coenzyme Q10

A critical component of the OXPHOS reaction pathway, CoQ10 serves to shuttle electrons between two “stations” along the mitochondrial inner membrane on the pathway to ATP formation. Without adequate CoQ10 supply, electron transport may slow, resulting in fewer ATP molecules being produced, and ultimately less available cellular energy.

CoQ10 supplementation has been shown to improve outcomes in several neurodegenerative disorders involving loss of mitochondrial function, such as Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.302,303 Some animal data provides evidence for CoQ10’s potential for preserving cognitive function in conditions such as experimental Alzheimer’s disease.304



The amino acids lysine and methionine are biochemically conjoined in vivo to form the compound carnitine. Carnitine is essential for ensuring that fatty acids are transported into the mitochondrial matrix where they fuel aspects of OXPHOS, but under certain conditions, including age-related cognitive decline, endogenous synthesis may be insufficient to support optimal fatty acid transport.

Acetyl-L-carnitine optimizes cognition by acting upon multiple facets of neuronal function, including enhancing efficiency of cholinergic neurotransmission,311stabilization of neuronal mitochondrial membranes,312 increasing neural antioxidant defenses,313 and enhancing neuron growth through sensitization to neurotrophic factors.314,315

A meta-analysis (comprehensive systematic review) of randomized, controlled human clinical trials involving data from 21 studies and data for over 1,200 subjects with mild cognitive impairment or mild to moderate Alzheimer’s disease provides unequivocal evidence that supplementation with acetyl-L-carnitine ameliorates cognitive deficits observed during aging and during pathological brain deterioration.316 The reviewers found that daily doses of acetyl-L-carnitine ranging from 1.5 – 3.0 grams consistently provided a statistically significant benefit over placebo for preserving cognition as assessed by multiple standardized tests. Moreover, there was a clear trend for a cumulative effect of acetyl-L-carnitine supplementation over time, suggesting that long-term use of acetyl-L-carnitine may provide the greatest benefit.



Like the omega-3’s EPA and DHA, phosphatidylserine is an especially important component of cellular membranes. In the brain phosphatidylserine conjugates with DHA and helps maintain the proper electrical gradient along neuronal membranes, thus facilitating proper neural communication.317 Human clinical trials have found that oral phosphatidylserine in doses ranging from 200 mg to 600 mg daily improves cognitive function in aging subjects with cognitive impairment.318,319,320


Bacopa Monnieri

In India, where the Bacopa monnieri herb grows, the leaves are held in high regard, and have long been believed in Ayurvedic medical tradition to promote cognitive health. More recently, modern scientific inquiry into the origins of these Ayurvedic tenets has revealed that the herb supports brain function through various mechanisms.

Bacopa is rich in free radical scavenging compounds including polyphenols and sulfur-based molecules, and so may ameliorate the oxidative stress generated by the brains’ intense metabolic rate.327 It also contains various phytochemicals with known anti-inflammatory properties, such as luteolin and apigenin.328,329 Several human clinical trials have revealed cognitive-enhancing, and memory improving effects of supplementation with Bacopa extract.

In one double-blind, placebo-controlled trial, daily doses of 300 mg of Bacopa extract significantly improved visual information processing speed, memory consolidation, and lessened anxiety in healthy individuals after 12-weeks of supplementation.330 


Glyceryl Phosphoryl Choline

Glyceryl phosphoryl choline (GPC) is a form of choline that is naturally present in all the body’s cells. Among aging adults, the rationale for GPC therapy goes back to the hypothesis, developed more than 30 years ago, that declining levels of acetylcholine—and a concurrent decrease in the number of neurons that are its intended target—are responsible for a range of cognitive deficits.337 Acetylcholine is an essential neurotransmitter involved in muscle control, sleep, and cognition. Research has shown that GPC is a precursor of acetylcholine that is safe and well tolerated.338 A review of 13 published studies, involving more than 4000 participants, found that patients taking GPC exhibited neurological improvement and relief of clinical symptoms of chronic cerebral deterioration that was clearly superior to placebo and “superior or equivalent” to that obtained with prescription drugs. The same authors found that GPC was superior to choline and lecithin and that it deserved wider study as a therapy for stroke patients seeking to regain full cognitive function.339



Even the healthiest diets may not provide the optimal levels of micronutrients, vitamins, and minerals needed to support healthy brain function. A comprehensive multi-vitamin supplement may help to fill these nutritional gaps and ameliorate some consequences of insufficient dietary nutrition. In a double-blind, controlled clinical trial involving over 200 healthy middle-aged individuals subjects were given either a multi-vitamin or placebo for more than two months, and both groups were then assessed for cognitive function. It was shown that those taking the multi-vitamin displayed less fatigue during extended cognitive challenges, and were also more accurate. Also, those taking multi-vitamins were able to more quickly complete mathematical processing tests than subjects receiving placebo.346​​​​



Age-related cognitive decline is associated with reduced synaptic plasticity in the brain. A novel form of magnesium, magnesium-L-threonate, has been shown to enhance signaling through pathways that promote synaptic plasticity.347 Also, Alzheimer’s disease is associated with magnesium deficit and accumulation of amyloid-beta plaques in the brain.348 Magnesium-L-threonate has been shown to boost brain magnesium levels and enhance the clearance of amyloid-beta in preclinical and laboratory research.349,350 In a mouse model of Alzheimer’s disease, treatment with magnesium-L-threonate reduced amyloid-beta accumulation, prevented synapse loss, and reduced memory decline. Magnesium-L-threonate conferred benefit even when given to mice with advanced-stage Alzheimer’s-like disease.351  This novel magnesium compound was also shown to combat inflammatory processes in the brain by preventing upregulation of the inflammatory mediator TNF-α.350



Primary Suggestions

  • Support Brain Health:
    • Alpha-Glyceryl Phosphoryl Choline (A-GPC)
    • Phosphatidylserine
    • Gastrodin
    • Grape Seed Extract
    • Wild Blueberry Extract
    • Ashwagandha root and leaf extract
    • Fish Oil
  • Support Dopamine:
    • Wild green oat extract
  • Support Brain Magnesium:
    • Magnesium-L-Threonate

 Additional Support

  • Phosphatidylserine: 100 – 200 mg daily
  • Acetyl-L-carnitine: 1500 – 3000 mg daily
  • Trans-Resveratrol: 250 – 500 mg daily
  • Blueberry: standardized extract: 500 – 1000 mg daily
  • Green tea: standardized extract: 725 – 1450 mg daily
  • B-vitamin complex: Per label instructions
  • Complete multi-vitamin: Per label instructions
  • CoQ10 (as ubiquinol): 100 – 300 mg daily
  • Bacopa: standardized extract: 450 – 900 mg daily




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